Iron deficiency anemia is a common pathological manifestation in patients with chronic kidney disease (CKD) and is associated with significant increase in cardiac morbidity and mortality (see, e.g., Harnett et al., Am. J. Kidney Dis., 25, S3-S7, 1995; Xue et al., Am. J. Kidney Dis., 40, 1153-1161, 2002; Abramson et al., Kidney Int., 64, 610-615, 2003). Primary causes of anemia in CKD patients are iron deficiency and insufficient erythropoiesis (see, e.g., Eschbach, Kidney Int., 35, 134-148, 1989; Fishbane et al., Am. J. Kidney Dis., 29, 319-333, 1997). Iron deficiency may occur when body iron stores are depleted in CKD patients undergoing hemodialysis due to excess loss of blood. Iron deficiency may also occur due to inflammation induced low mucosal oral iron absorption and decreased mucosal iron transfer in CKD patients undergoing hemodialysis (see e.g., Kooistra et al., Nephrol. Dial. Transplant., 13, 82-88, 1998). Demand for iron is also increased in the production of red blood cells in response to the treatment with erythropoiesis stimulating agents (ESA) in CKD patients. Thus, iron deficiency is an inevitable consequence in patients undergoing hemodialysis and ESA treatment. Correcting iron deficiency is a necessary step for the treatment of anemia in CKD patients (see e.g., Silverberg et al., Kidney Int. Suppl., 69, S79-S85, 1999; Spinowitz et al., J. Am. Soc. Nephrol., 19, 1599-1605, 2008).
The oral iron absorption process occurs in two steps: (1) absorption of iron in the gut by the epithelial cells, and (2) transport of iron from the cells to the systemic circulation. In the first step, oral iron is absorbed and taken up by enterocytes in the proximal duodenum via the epithelial divalent metal ion transporter DMT1 (or DCT1) (see e.g., Gunshin et al., Nature, 388(6641), 482-488, 1997). Oral iron in the gut is first converted from Fe3+ to Fe2+ by a ferri-reductase enzyme and then binds to DMT1 for its transport into the epithelial cells. (2) In the second step, intracellular iron is either taken up by the ubiquitous iron protein ferritin and stored in the cytoplasm, or is transported into the circulation via the basolateral cell surface transporter ferroportin (see, e.g., Abboud et al., J. Biol. Chem., 275(26), 19906-19912, 2000; Donovan et al., Nature. 403(6771), 776-781, 2000). Release of iron to the circulation is tightly regulated by the peptide hepcidin secreted by liver. Hepcidin binds to ferroportin thereby initiating ferroportin endocytosis and lysosomal degradation (see, e.g., Nemeth et al., Science, 306(5704), 2090-3, 2004). Thus high expression of hepcidin lowers the distribution of ferroportin in the basolateral membrane thereby reducing the release of iron from the duodenal mucosal cells into the circulation.
The bioavailability of oral iron is limited by both the absorption efficiency of the enterocytes and hepcidin regulated release of iron from the mucosal cells. Although oral iron bioavailability was found to be approximately 22% in healthy subjects (see, e.g., Hansen et al., Phys. Med. Biol., 37(6), 1349-1357, 1992) this value will be significantly lower if the absorption and release of iron from the enterocytes is inhibited. Inflammatory cytokine IL-6, a product of macrophages activated by inflammation, is believed to upregulate hepcidin synthesis thereby limiting the release of intracellular iron (see, e.g., Nemeth et al., J. Clin. Invest., 113(9):1271-1276, 2004). Correlation between inflammatory cytokine IL-6 and poor oral iron absorption (reduced more than 60% based on serum iron AUC value) has been observed in patients suffering from Crohn's disease (see, e.g., Semrin et al., Inflamm. Bowel Dis., 12(12), 1101-1106, 2006). Inflammation is prevalent in CKD patients (see, e.g., Oberg et al., Kidney Int., 65(3), 1009-1016, 2004) and bioavailability of conventional oral iron formulation is severely affected primarily through the activation of inflammation-hepcidin pathway described above. Intravenous (IV) iron therapy, however, is effective in dialysis patients as it is able to circumvent the inflammation-hepcidin regulatory pathway by delivering iron directly to the circulation.
Current methods of oral iron therapy typically suffer from low bioavailability of the iron, making them ineffective for the treatment of anemia in CKD patients (see, e.g., Van Wyck et al., Kidney Int., 68, 2846-2856, 2005; Charytan et al., Nephron. Clin. Pract., 100, c55-c62, 2005). Thus, the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) has recommended the use of IV iron therapy as the primary means of correcting anemia in dialysis patients (see, e.g., NKF-KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease, 2007 update, www.guideline.gov (National Guideline Clearinghouse)). Anemia, however, is not limited to patients with CKD. Inflammation of the stomach lining such as in gastritis, or celiac disease, and any other abnormalities in the metal ion transporters responsible for iron transport renders oral iron absorption insufficient leading to anemia.
Thus, there is a continuing need to develop effective and well-tolerated oral treatments for patients with iron deficiency (for instance, anemic patients with CKD).